From the Gertrude H. Sergievsky Center (Drs Tang, Stern, Marder, Bell, and Mayeux), the Taub Center for Alzheimer's Disease Research (Drs Stern, Marder, Bell, Gurland, Lantigua, Andrews, Tycko, and Mayeux and Ms Feng), the Divisions of Biostatistics (Dr Tang) and Epidemiology (Dr Mayeux), School of Public Health, the Departments of Neurology (Drs Stern, Marder, Bell, and Mayeux), Psychiatry (Drs Stern, Gurland, and Mayeux), Medicine (Dr Lantigua), and Pathology (Ms Feng and Dr Tycko), and the Morris W. Stroud III Center for the Study of Quality of Life (Drs Gurland and Lantigua), Columbia University College of Physicians and Surgeons and Columbia-Presbyterian Medical Center, and the Division of Statistics, New York State Psychiatric Institute (Dr Andrews), New York, NY.

ABSTRACT

Context.— Although the association between Alzheimer disease (AD) and the apolipoprotein
E ∊4 (APOE-∊4) allele has been confirmed
worldwide, it appears to be inconsistent among African Americans, Hispanics,
and Nigerians.

Objective.— To investigate the association between the APOE-∊4
allele and AD in elderly African Americans, Hispanics, and whites.

Design.— Prospective, population-based, longitudinal study over a 5-year period
(1991-1996).

Setting.— The Washington Heights–Inwood community of New York City.

Participants.— A total of 1079 Medicare recipients without AD or a related disorder
at baseline.

Main Outcome Measures.— Risk of clinically diagnosed AD in the 3 ethnic groups and among individuals
with and without an APOE-∊4 allele.

Results.— Compared with individuals with the APOE-∊3/∊3
genotype, the relative risk (RR) of AD associated with 1 or more copies of
the APOE-∊4 allele was significantly increased
among whites (RR, 2.5; 95% confidence interval [CI], 1.1-6.4), but not among
African Americans (RR, 1.0; 95% CI, 0.6-1.6) or Hispanics (RR, 1.1; 95% CI,
0.7-1.6). In the absence of the APOE-∊4 allele,
the cumulative risks of AD to age 90 years, adjusted for education and sex,
were 4 times higher for African Americans (RR, 4.4; 95% CI, 2.3-8.6) and 2
times higher for Hispanics (RR, 2.3; 95% CI, 1.2-4.3) than for whites. In
the presence of an APOE-∊4 allele, the cumulative
risk of AD to age 90 years was similar for individuals in all 3 ethnic groups.

Conclusion.— The presence of an APOE-∊4 allele is a
determinant of AD risk in whites, but African Americans and Hispanics have
an increased frequency of AD regardless of their APOE
genotype. These results suggest that other genes or risk factors may contribute
to the increased risk of AD in African Americans and Hispanics.

Figures in this Article

ALTHOUGH the association between Alzheimer disease (AD) and the apolipoprotein
E ∊4 (APOE-∊4) allele has been confirmed
worldwide, it has been found to be weak or nonexistent among African Americans
living in New York City1- 3
and Indiana4 and among Nigerians.5
Hispanics of Caribbean origin also have an inconsistent association between
AD and the APOE-∊4 allele.2,3
While other genetic or environmental factors might account for the reduction
in APOE-∊4–related AD risks in these ethnic
groups compared with whites, none have been identified. This prospective study
was designed to compare the cumulative risk of AD by APOE genotypes among elderly African Americans, Hispanics, and whites residing
in a New York City community. Based on our previous cross-sectional studies,1- 3 we hypothesized that
the risk of AD associated with the APOE-∊4 allele
would be lower for African Americans and Hispanics than for whites.

METHODS

Subjects and Setting

Participants were healthy Medicare recipients without dementia in 3
contiguous ZIP codes within the community of Washington Heights in northern
New York City. According to the 1990 census, 9349 people older than 65 years
lived in this area. The Health Care Financing Administration provided access
to a random sample of approximately half of these recipients. In this group,
4865 individuals were then divided into 37 identical replicates, representing
the demographic characteristics of the cohort, sent a letter from the Health
Care Financing Administration explaining that they had been randomly selected
to participate in a study of aging by investigators at Columbia University,
New York, NY. Subsequently, it was determined that 470 (9.7%) had died, 896
(18.4%) no longer lived in the region, 47 (1%) were ineligible, and 1324 (37%)
did not wish to participate. The frequency of participation did not differ
by sex or subsample. The proportions of individuals within each ethnic group,
as identified from Health Care Financing Administration records, differed
only slightly between the total sample and those who participated (total sample:
African American, 35.4%; Hispanic, 35.4%; white, 29.2%; participants: African
American, 35.2%; Hispanic, 38.9%; white, 25.8%).

For the 2128 subjects who participated in the initial phase of the study,
a 90-minute, in-person interview of general health and function was completed.
This structured interview also included questions about years of formal education
and lifetime occupation. The interview was followed by a standardized clinical
assessment, including a medical history, physical and neurologic examination,
and brief (approximately 1 hour) neuropsychological battery previously developed
for use in this community.6,7
These same clinical assessments were used in the annual follow-up of all participants.
This study was conducted from 1991 through 1996. The interviews were conducted
in either English or Spanish. The Columbia University Institutional Review
Board reviewed and approved this project. All individuals provided written
informed consent.

Diagnosis

The data from the initial and follow-up examinations and interviews
and any existing medical records and imaging studies were used at a consensus
conference of physicians and neuropsychologists to establish diagnoses. The APOE genotypes were never available to the clinicians during
the diagnostic process. The diagnosis of dementia or the specific clinical
diagnosis of AD was based on standard research criteria8(pp205-224)9 and required evidence of cognitive deficit on the
neuropsychological test battery as well as evidence of impairment in social
or occupational function. Patients who met the criteria9
for probable or possible AD with a clinical dementia rating (CDR) scale (range,
0-5) score of 0.5 or higher10 were considered
to have a clinical diagnosis of AD.

Ethnic Group

Ethnic group was classified by self-report using the format of the 1990
US Census.11 Individuals were then asked whether
they were of Hispanic origin. Using this information, individuals were separated
into 3 ethnic groups: African American (non-Hispanic), Hispanic, or white
(non-Hispanic). Individuals were also asked to identify the country of their
birth.

Family History Assessment

A structured family history interview for AD and other neurologic disorders
in first-degree relatives (parents and full siblings) was conducted directly
with each participant at the first interview.12

Genotyping

Genomic DNA was amplified by polymerase chain reaction and subjected
to Cfo I restriction analysis using APOE primers
and conditions modified from those described by Hixson and Vernier.13

Data Analysis

Demographic characteristics were compared using χ2 tests
for categorical variables and analysis of variance for continuous variables.14 Age, ethnic group, and education were compared among
those who did and did not develop AD. APOE allele
frequencies were determined by counting alleles and calculating sample proportions. APOE allele frequencies were compared among individuals
who did and did not develop AD as well as between ethnic groups using χ2 tests.

The Cox proportional hazards model15
was used to compute the relative risks (RRs) of AD. As recommended for longitudinal
investigations,16 the time-to-event variable
was age at onset of AD, which required no further age adjustment. Among those
who did not develop AD, we right-censored the age at death or the age at the
last examination. Survival analysis was used to plot the cumulative incidence
of AD at each age interval. Proportional hazards were estimated for APOE genotypes with and without an ∊4 allele and adjusted
by education, ethnic group, and sex. A second series of proportional hazards
models was stratified by the presence or absence of an APOE-∊4 allele to estimate the relative risk by ethnic group using
whites as the reference. Proportional hazards models were stratified by the
median number of years of formal education. Subsequent proportional hazards
models included adjustments for a family history of an AD-like dementia; a
medical history of hypertension, myocardial infarction, or head injury; and
a history of smoking. Martingale methods were used to check the proportional
hazards assumption.17

RESULTS

Among the 2128 individuals interviewed at baseline, 392 (18.4%) were
found to be demented, 155 (7.3%) died after the initial examination, 122 (5.7%)
refused to have genotyping performed, and 237 (11.1%) refused subsequent follow-up.
The proportions of individuals who were demented at baseline differed among
the 3 ethnic groups (African Americans, 24%; Hispanics, 18%; whites, 11%; P<.001), as did the proportions of those who died after
the baseline evaluation (African Americans, 12%; Hispanics, 4%; whites, 9%; P<.001). Compared with Hispanics, a higher proportion
of African Americans and whites refused genotyping (4% vs 7% and 8%, respectively; P<.001) or were unavailable for follow-up (8% vs 15%
and 16%, respectively; P<.001). We also found
25 individuals (1.2%) with Parkinson disease, 117 (5.5%) with stroke, and
1 with both Parkinson disease and stroke. Only stroke was more frequent among
African Americans than either Hispanics or whites (15% vs 7.8% and 8%, respectively; P<.001). This left 1079 healthy elderly (731 women and
348 men) without dementia available for this follow-up investigation.

The mean age of the participants at the beginning in this investigation
was 75.3 (SD, 5.8) years and the mean years of education was 8.6 (SD, 4.4).
The ethnic distribution of the cohort by self-report differed from that provided
by the Health Care Financing Administration. Among the 1079 healthy elderly,
16.8% described themselves as African American, 61.2% as Hispanic, and 22%
as white. The majority (84%) of those identified as Hispanic were of Caribbean
origin, while the remainder were from Mexico and Central America. The mean
duration of follow-up was 2.4 (SD, 1.2) years (range, 1-5 years).

Probable or possible AD developed in 221 individuals (20.5%) over the
follow-up period. Both probable and possible AD occurred significantly more
frequently among African Americans and Hispanics than among whites (probable
AD: 10.5%, 7.6%, and 3.4%, respectively; possible AD: 18.8%, 14.4%, and 6.3%,
respectively; χ2=26.4; P=.001). The
individuals who developed AD were older at the initial interview and had less
education than those who did not develop AD (age: 78.0 [6.5] vs 75.3 [5.8]
years; education: 6.2 [4.5] vs 8.6 [4.4] years; P=.001
for both). The proportions of men and women who developed AD were similar.

APOE allele frequencies differed significantly
between ethnic groups (P=.009) but were not significantly
different between those who developed AD and those who remained free of dementia
(Table 1). However, using the APOE-∊3/∊3 genotype as the reference, the RR
of AD to age 90 years associated with APOE-∊4
homozygosity was significantly increased (RR, 2.8; 95% confidence interval
[CI], 1.3-6.0), while that associated with APOE-∊4
heterozygosity was not elevated (RR, 1.1; 95% CI, 0.8-1.6). Adjustment for
ethnic group and years of education did not change the point estimates.

Table Graphic Jump LocationTable 1.—APOE Allele Frequencies by
Ethnic Group Among Individuals Who Did and Did Not Develop Alzheimer Disease*

The distribution of APOE genotypes also differed
significantly by ethnic group (χ2= 23.5, df=10, P=.009) (Table 2). Using the APOE-∊3/∊3
genotype as the reference, the RR of AD to age 90 years associated with 1
or more APOE-∊4 alleles was increased for whites
(RR, 2.5; 95% CI, 1.1-6.4) but not for African Americans (RR, 1.0; 95% CI,
0.6-1.6) or Hispanics (RR, 1.1; 95% CI, 0.7-1.6). There were too few individuals
with the APOE-∊4/∊4 genotype within each
ethnic group to derive a meaningful independent RR estimate (Table 2).

In a second analysis we examined differences in disease risk across
ethnic groups within specific APOE genotypes. Among
individuals with 1 or more APOE-∊4 alleles (APOE-∊4/∊4, -∊4/∊-2, and -∊4/∊3),
there was no significant difference in the RR of AD to age 90 years for African
Americans and Hispanics compared with whites (African Americans: RR, 1.6;
95% CI, 0.7-3.8; Hispanics: RR, 0.8; 95% CI, 0.4-1.9), even after adjustment
for education and sex. Thus, the cumulative risk of AD to age 90 years among
individuals with an APOE-∊4 allele was similar
for all 3 ethnic groups.

When the analysis was repeated, restricted to individuals without an APOE-∊4 allele (APOE-∊3/∊3,
-∊2/∊3, and -∊2/∊2), the relative risk of AD to age 90
years, adjusted for education and sex, was significantly higher for African
Americans (RR, 4.4; 95% CI, 2.3-8.6) and Hispanics (RR, 2.3; 95% CI, 1.2-4.3)
than for whites. Similar results were obtained when the analysis was restricted
to individuals with the APOE-∊3/∊3 genotype
(African Americans: RR, 4.3; 95% CI, 2.0-8.9; Hispanics: RR, 2.2; 95% CI,
1.2-4.3). Figure 1 illustrates that
among individuals without an APOE-∊4 allele,
the cumulative incidence of AD to age 90 years was significantly higher among
African Americans and Hispanics than among whites (log-rank test, P<.001).

Figure 1.—Cox proportional hazards model of the cumulative
incidence of Alzheimer disease to age 90 years among individuals with the
apolipoprotein E (APOE)–∊3/∊3 genotype
by ethnic group, controlled for education. In this analysis, patients with
both mild and moderate disease (clinical dementia ratings of 0.5 and 1) were
included as cases. The differences between African Americans and Hispanics
vs whites were significant (log-rank test, P<.001).

To determine if differences in education might account for the apparent
increased risk of AD among African Americans and Hispanics compared with whites
for individuals without an APOE-∊4 allele, we
recalculated RRs for AD by ethnic group among individuals with the APOE-∊3/∊3 genotype, adjusting for the number of years of
education. The RRs for AD among African Americans and Hispanics were identical
to the previous estimates, implying no interaction between ethnic group and
education.

The frequency of a family history of dementia differed slightly but
not significantly across the 3 ethnic groups (African Americans, 15%; whites,
18.7%; Hispanics, 18.3%; χ2=0.6, P=.7)
and across APOE genotypes. A history of hypertension
was more frequent among African Americans (63.5%) and Hispanics (61.7%) than
among whites (46%) (χ2=8.5, P=.001),
but this was not associated with the development of AD when entered as a covariate
in the proportional hazards model. When family history of an AD-like illness,
medical history of myocardial infarction or head injury, and history of smoking
were added to the model, these likewise had no effect on the risk of development
of AD.

Individuals who developed AD during follow-up included patients with
both mild (CDR score, 0.5) and more advanced (CDR score, 1) disease. The number
of patients with mild disease (n=144) might have influenced the differences
between ethnic groups, because diagnostic accuracy may be less than optimal
in the initial stage of the disease. We recalculated the RRs, reclassifying
patients with mild disease (CDR score, 0.5) as free of dementia. Figure 2 illustrates the difference in cumulative
incidence of AD to age 90 years by ethnic group among individuals with and
without an APOE-∊4 allele (log-rank test, P=.001). Among individuals with an APOE-∊4 allele, African Americans and Hispanics had a slightly but
not significantly higher risk of AD to age 90 years compared with whites (African
Americans: RR, 1.9; 95% CI, 0.3-9.5; Hispanics: 1.4; 95% CI, 0.3-6.9). However,
among individuals without an APOE-∊4 allele,
both African Americans and Hispanics had a significantly higher risk of AD
to age 90 years compared with whites (African Americans: RR, 4.4; 95% CI,
1.6-12.4; Hispanics: RR, 2.3; 95% CI, 1.0-6.1).

Figure 2.—Cox proportional hazards model of the cumulative
incidence of Alzheimer disease to age 90 years among individuals with and
without an apolipoprotein E (APOE)–∊4
allele by ethnic group, controlled for education. Only patients with moderate
disease (clinical dementia rating of 1) were classified as cases, while patients
with mild disease (clinical dementia rating of 0.5) were reclassified as free
of dementia. Among individuals with and without an APOE-∊4 allele, the differences between African Americans and Hispanics
vs whites were significant (log-rank test, P=.001).
Among individuals with an APOE-∊4 allele, African
Americans and Hispanics had a slightly but not significantly higher cumulative
incidence of Alzheimer disease to age 90 years vs whites (African Americans:
RR, 1.9; 95% confidence interval [CI], 0.3-9.5; Hispanics: RR, 1.4; 95% CI,
0.3-6.9). Among individuals without an APOE-∊4
allele, both African Americans and Hispanics had a higher cumulative incidence
of Alzheimer disease to age 90 years than whites (African Americans: RR, 4.4;
95% CI, 1.6-12.4; Hispanics: RR, 2.3; 95% CI, 1.0-6.1).

COMMENT

African Americans and Hispanics with an APOE-∊4
allele were as likely as whites with an APOE-∊4
allele to develop AD by age 90 years in this study of elderly individuals.
However, in the absence of an APOE-∊4 allele,
African Americans and Hispanics were 2 to 4 times more likely than whites
to develop AD by age 90 years. This increase in risk was not related to differences
in education or the presence of a family history of an AD-like dementia. While
hypertension was more frequent among African Americans and Hispanics than
among whites, it was not related to the risk of AD. These observations provide
evidence that, in addition to the APOE-∊4 allele,
previously unidentified genes or other risk factors may contribute to the
etiology of AD among African Americans and Hispanics.

Gurland et al18,19 reported
a relative increase in the prevalence and incidence rate of AD and other dementias
among African Americans and Hispanics compared with whites in this community.
Differences in the prior educational experience of individuals in these ethnic
groups could have influenced psychometric testing for dementia.20
However, Gurland et al19 also observed a parallel
decline in activities related to daily function among individuals with mild
and moderate dementia compared with those who remained free of dementia. Because
we used the same diagnostic assessments, it is unlikely that the differences
between ethnic groups in the frequency of AD reported here are the result
of inappropriate diagnosis among African Americans and Hispanics.

Since the first report of an association between the APOE-∊4 allele and AD, the association has been confirmed by investigators
throughout the world.21- 27
Indeed, APOE-∊4 has emerged as one of the most
important risk factors for AD. There have been rare exceptions; we1- 3 previously reported
a weaker association between AD and APOE-∊4
among African Americans and Hispanics compared with whites in this community.
In contrast, Hendrie et al25 found an increased
risk of AD associated with APOE-∊4 among a small
group of African Americans in Indiana, but no association between AD and APOE-∊4 was observed among Nigerians.5
In a subsequent study4 of African Americans
in Indiana, the association between APOE-∊4
and AD was greatly reduced, similar to our earlier observations. Farrer et
al28 recently completed a worldwide meta-analysis
of the relationship between APOE-∊4 and AD using
numerous published and unpublished studies. They concluded that APOE-∊4 was an important determinant of AD risk for men and women
after age 60 years. They also confirmed that APOE-∊4
was strongly related to AD risk among whites and Asians but that the relationship
among African Americans and Hispanics remained comparatively inconsistent
and weak, supporting our earlier findings.

Previous studies of AD and APOE-∊4 have
computed risks using a reference genotype, such as APOE-∊3/∊3. It is possible that previous observations of an attenuated APOE-∊4 association among African Americans and Hispanics
resulted from an increase in the frequency of AD among individuals with other APOE alleles.

A slight increase in AD risk associated with the APOE-∊2 allele has been observed among individuals with early-onset
disease,29 and we previously reported an association
between this allele and AD among African Americans and Hispanics.2 van Duijn et al29 attributed
the increased risk of AD among individuals with the APOE-∊2 allele to a survival effect. Scott et al30
reported no association between AD and the APOE-∊2
allele, but they used a cross-sectional design that could not examine the
effects of survival. While there is no consensus,31
the APOE genotype may influence survival among patients
with AD.32 The prospective nature of our study
lessened the possibility of a survival effect, but we draw no firm conclusions
regarding the effect of the APOE-∊2 allele on
AD risk because of the low frequency of this allele in the study population.

Two studies, one autopsy-based33 and
the other clinical,34 have previously compared
the rates of AD among African Americans and whites in the United States. De
la Monte et al33 reported that AD was significantly
more frequent among whites than African Americans at autopsy, but the pathologic
criteria for AD and multi-infarct dementia were not described, and diagnoses
were simply recorded from existing reports. In a clinical study, Bohnstedt
et al34 found the rates of AD to be comparable
among African Americans and whites once differences in education were considered.
We adjusted for education as a continuous variable and also stratified by
the median, but the higher risk of AD in the absence of the APOE-∊4 allele persisted. Still, some unmeasured socioeconomic
factors or cultural attributes may contribute to the higher frequency of disease
observed in this study.

This study is not without limitations. One is the lack of autopsy confirmation
of AD. The presence of an APOE-∊4 allele in
whites with probable or possible AD increases the likelihood of confirmation
of the diagnosis.35 No similar data were available
for African Americans or Hispanics. However, a slight decrease in the accuracy
of diagnosis would not account for the 2-fold to 4-fold differences among
patients without the APOE-∊4 allele. Because
fewer Hispanics were unavailable for follow-up or refused genotyping, a larger
number were included in the study, which could have contributed to the higher
observed frequency of AD in this group. We do not favor this explanation for
2 reasons: (1) There were significantly more Hispanic than white patients
with prevalent AD at baseline, which supports the findings in the prospective
study. (2) The proportions of African Americans and whites who were unavailable
for follow-up or who refused genotyping were comparable, yet the cumulative
risk of AD was significantly higher among African Americans.

Our results suggest that as African Americans and Hispanics age, the
frequency of AD in these populations may increase disproportionately. The
elderly Hispanic population in the United States has been increasing more
rapidly than that of other ethnic groups.36
Because of the decline in function and the expense related to AD, identification
of other genetic and environmental determinants of this disease among African
Americans and Hispanics is an important next step.

Figures

Figure 1.—Cox proportional hazards model of the cumulative
incidence of Alzheimer disease to age 90 years among individuals with the
apolipoprotein E (APOE)–∊3/∊3 genotype
by ethnic group, controlled for education. In this analysis, patients with
both mild and moderate disease (clinical dementia ratings of 0.5 and 1) were
included as cases. The differences between African Americans and Hispanics
vs whites were significant (log-rank test, P<.001).

Figure 2.—Cox proportional hazards model of the cumulative
incidence of Alzheimer disease to age 90 years among individuals with and
without an apolipoprotein E (APOE)–∊4
allele by ethnic group, controlled for education. Only patients with moderate
disease (clinical dementia rating of 1) were classified as cases, while patients
with mild disease (clinical dementia rating of 0.5) were reclassified as free
of dementia. Among individuals with and without an APOE-∊4 allele, the differences between African Americans and Hispanics
vs whites were significant (log-rank test, P=.001).
Among individuals with an APOE-∊4 allele, African
Americans and Hispanics had a slightly but not significantly higher cumulative
incidence of Alzheimer disease to age 90 years vs whites (African Americans:
RR, 1.9; 95% confidence interval [CI], 0.3-9.5; Hispanics: RR, 1.4; 95% CI,
0.3-6.9). Among individuals without an APOE-∊4
allele, both African Americans and Hispanics had a higher cumulative incidence
of Alzheimer disease to age 90 years than whites (African Americans: RR, 4.4;
95% CI, 1.6-12.4; Hispanics: RR, 2.3; 95% CI, 1.0-6.1).

Tables

Table Graphic Jump LocationTable 1.—APOE Allele Frequencies by
Ethnic Group Among Individuals Who Did and Did Not Develop Alzheimer Disease*

Letters

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